Genetic factors determining hepatitis B carrier status.

摘要

The outcome of Hepatitis B virus (HBV) infection is heterogeneous. Only a fraction of HBV infected individuals (0.1-0.5% in North American Caucasians, 10-15% in Asians) become persistently infected Hepatitis B surface antigen (HBsAg) carriers for unknown reasons. Such individuals fail to mount an antibody response to HBsAg. In addition, approximately 40% of HBsAg carriers with hepatic lesions eventually develop cirrhosis and the reasons are again unknown. Multiple predispositional factors of genetic and environmental origin may be involved. Human Leukocyte Antigen (HLA) may play a role in both immune response to HBsAg and in disease progression. The presence of the ALDH2*2 allele suppresses the function of aldehyde dehydrogenase (ALDH2) and leads to elevated levels of acetaldehyde, which is thought to be responsible for alcohol toxicity. This study investigated: (1) the association of alleles at HLA-DRB1, DQA1, and DQB1 loci with the initial immune response to HBsAg, (2) the association of alleles at HLA-DRB1, DQA1 and DQB1 loci with the progression toward cirrhosis among HBsAg asymptomatic carriers and (3) the role of the ALDH2*2 allele and alcohol consumption in the progression of HBV-associated cirrhosis. These studies were performed on Taiwanese who were HBV-associated cirrhotic patients, on HBsAg asymptomatic carriers, and on subjects seroconverted to antibody to HBsAg. Frequencies of HLA class II alleles and the ALDH2*2 allele were determined by sequence-specific oligonucleotide probe (SSOP) or single-strand conformation polymorphism (SSCP) analysis. Alcohol consumption information was obtained by a questionnaire modified from the NIAAA household survey questionnaire. HLA-DR13 was found to have a protective role against HBsAg carrier status after HBV infection, with an odds ratio of 0.27. HLA-DR7 was identified as a susceptibility allele in the progression to cirrhosis among HBsAg carriers with an odds ratio of 1.94. HBsAg carriers with the ALDH2*2 allele had a higher risk (OR = 4.0) in the progression to cirrhosis if they consumed modest levels ({dollar}>{dollar}18 g/day) of alcohol. An age adjusted logistic regression analysis which included HLA-DR7, ALDH2*2 and alcohol consumption levels suggested confounding interactions in the progression to cirrhosis among HBsAg carriers. This study identifies an interplay of HLA genotype, ALDH2 genotype and alcohol consumption in the clinical course of HBV infection and the progression to cirrhosis.